ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1
ALS-linked mutant SOD1 induces ER stress- and ASK1-dependent motor neuron death by targeting Derlin-1
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DOI：
10.1101/gad.1640108
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发表时间：
2008-06-01
影响因子：
10.5
通讯作者：
Ichijo, Hidenori
中科院分区：
文献类型：
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作者：
Nishitoh, Hideki;Kadowaki, Hisae;Ichijo, Hidenori
Cu/Zn-超氧化物歧化酶（SOD 1）的突变是家族性肌萎缩侧索硬化症（ALS）的原因。突变体SOD 1蛋白（SOD 1（mut））诱导运动神经元死亡，尽管SOD 1（mut）诱导细胞死亡的分子机制仍然存在争议。在这里，我们表明，SOD 1（mut）特异性相互作用与Derlin-1，内质网（ER）相关的降解（ERAD）机制的一个组成部分，并触发ER应激通过ERAD功能障碍。SOD 1（mut）诱导的内质网应激激活了凋亡信号调节激酶1（ASK 1）依赖的细胞死亡途径。通过Derlin-1衍生的寡肽干扰SOD 1（mut）和Derlin-1之间的结合抑制SOD 1（mut）诱导的ER应激、ASK 1激活和运动神经元死亡。ASK 1的缺失减轻了运动神经元的丢失，延长了SOD 1（mut）转基因小鼠的寿命。这些发现表明，ER应激诱导的ASK 1激活，这是由Derlin-1与SOD 1（mut）的特异性相互作用触发的，对家族性ALS的疾病进展至关重要。
Mutation in Cu/Zn-superoxide dismutase (SOD1) is a cause of familial amyotrophic lateral sclerosis (ALS). Mutant SOD1 protein (SOD1(mut)) induces motor neuron death, although the molecular mechanism of SOD1(mut)-induced cell death remains controversial. Here we show that SOD1(mut) specifically interacted with Derlin-1, a component of endoplasmic reticulum (ER)-associated degradation (ERAD) machinery and triggered ER stress through dysfunction of ERAD. SOD1(mut)-induced ER stress activated the apoptosis signal-regulating kinase 1 (ASK1)-dependent cell death pathway. Perturbation of binding between SOD1(mut) and Derlin-1 by Derlin-1-derived oligopeptide suppressed SOD1(mut)-induced ER stress, ASK1 activation, and motor neuron death. Moreover, deletion of ASK1 mitigated the motor neuron loss and extended the life span of SOD1(mut) transgenic mice. These findings demonstrate that ER stress-induced ASK1 activation, which is triggered by the specific interaction of Derlin-1 with SOD1(mut), is crucial for disease progression of familial ALS.